Treatment of vitiligo

ABSTRACT

Disclosed herein is a novel method of treating vitiligo by using an excimer laser that emits light in the UVB range. The invention includes a method of incrementally increasing exposure of affected vitiligo areas with UVB laser light from an excimer laser to restore pigmentation to skin areas afflicted with vitiligo.

This application is a continuation of U.S. Patent Application Ser. No.11/174,437, filed Jul. 1, 2005, which is a continuation of U.S. patentapplication Ser. No. 09/790,786, filed Feb. 22, 2001, which claimspriority under 35 U.S.C. §119 from U.S. Provisional Application Ser. No.60/184,971, filed Feb. 25, 2000, each of which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Vitiligo is a cutaneous disease in which there is a complete loss ofpigment in localized areas of the skin. This loss of pigment results inthe effected areas being completely white. This condition has apredilection for the skin around the mouth and eyes. The result iscosmetically disfiguring, especially for dark skinned people.Furthermore, the depigmented skin is sun sensitive, and thus is subjectto sunburns and skin cancer. In sum, vitiligo is both cosmetically andpractically distressing to patients afflicted with the disease.

In normal skin, varying shades of brown are seen (depending on aperson's race) representing the pigment melanin. This pigment isproduced by a cell type known as a melanocyte. In vitiligo, there is anabsence of melanocytes in the areas afflicted with the disorder. Anabsence of melanocytes results in an absence of melanin pigment, andthus the melanin-free area is white. Normal skin responds to ultravioletlight with an increase in the brown pigment melanin (tanning).Specifically, ultraviolet radiation stimulates melanocytes toproliferate and produce more melanin.

Attempts have also been made to “tan” vitiligo areas using ultravioletlight treatments. The ultraviolet spectrum is divided into two portions,“UVA” and “UVB,” which is light of 320-400 nm and 290-320 nm inwavelength, respectively. UVB is much more effective at producing a tanin normal skin. In normal skin, melanocytes reside in the epidermis,which is the outer layer of the skin. The epidermis is only 0.1 mmthick, so the melanocytes are very near the surface. UVB radiation canonly penetrate to about 0.1 mm, but this is sufficient to reach themelanocytes. In patients with vitiligo, these epidermal melanocytes aregone. In some cases, there are surviving melanocytes deeper in the skindown the hair follicles. These melanocytes may be several millimetersdeep. UVB cannot penetrate this deep in the skin to stimulate thesesurviving deep melanocytes. Exposure to UVB results in a sunburn at thesurface of the skin with no stimulation of these deep melanocytes. Thusattempts to repopulate the vitiligo areas with melanocytes deep in theskin in response to UVB exposure have failed. UVA will penetrate a bitdeeper in the skin than UVB. However, UVA is very poor at stimulatingmelanocytes to proliferate and migrate.

DESCRIPTION OF RELATED ART

The present invention uses an excimer laser to restore pigmentation toskin areas afflicted with vitiligo, and is an improvement over currenttreatments for vitiligo. Currently, treatments for vitiligo suffer froma number of drawbacks. For instance, Fitzpatrick's Dermatology inGeneral Medicine, Vol. 1, Chapter 89 (5^(th) ed., I. M. Freedberg etal., eds., 1999) teaches the use of sunscreens and cosmetic cover-upsincluding dyes and conventional makeup as a way to mask skin areasafflicted with vitiligo. However, the ability of sunscreens to minimizecontrast between normal skin and vitiligo-afflicted areas has beendisappointing. Sunscreens, as well as cosmetics and dyes, are notpermanent. These products tend to rub-off and have been of limited valuein areas such as the lower neck, wrists and hands. In addition, unlikethe present invention, sunscreens and cosmetics cover-ups do not attemptto treat vitiligo, but simply blend in the affected areas with thesurrounding skin. The prior art also teaches the use of topicalglucocortoids to treat isolated areas of vitiligo. Fitzpatrick'sDermatology in General Medicine. However, the overall results tend to bedisappointing. The present invention improves on these treatments byproviding a more permanent restoration of pigmentation to vitiligoaffected areas, with a relatively high rate of success.

Another known treatment for vitiligo attempts to increase the action ofUVA light by combining exposure to UVA with a chemical that is appliedto the skin to increase sensitivity to UVA. Fitzpatrick's Dermatology inGeneral Medicine, Vol. 1, Chapter 89 (5^(th) ed., I. M. Freedberg etal., eds., 1999). This chemical is known as psoralen, and psoralen andUVA together are known as PUVA. Specifically, high output UVA (320-400nm) light bulbs are utilized within an indoor phototherapy unit. Thepatient applies psoralen to the effected areas, then stands inside thephototherapy unit for exposure to the UVA light emitted by conventionaltube-style bulbs.

This type of PUVA treatment suffers from a number of drawbacks. Unlikethe present invention, PUVA treatment is to the whole body, not just thevitiligo areas. Therefore PUVA therapy has been associated with thedevelopment of skin cancers. PUVA treatment is also time-consuming; aminimum of 100 treatments, given 2-3 times per week over many months, isnecessary before any response is seen. In addition, this treatment hashad a relatively low success rate. Significantly less than 50% ofpatients will respond to this treatment. The present invention, however,treats only those skin areas afflicted with vitiligo, and thus minimizesthe risk of skin cancer. The present invention also is less timeconsuming, and enjoys a relatively higher success rate.

Topical PUVA also may be used to treat localized patches of vitiligo andconsists of applying a topical preparation of 8-methoxypsoralen to thepatch of vitiligo and exposing the patch to UVA radiation at intervalsof two to three times weekly. This type of PUVA treatment also has anumber of drawbacks. Erythema, blistering and hyperpigmentation ofsurrounding skin are common complications. In addition, the success rateis relatively low. Repigmentation is seen in only about half of treatedpatients. Westernof, W., et al., “Treatment of Vitiligo with UV-BRadiation vs. Topical Psoralen Plus UV-A,” Arch. Dermatol; 1997;133:1525-28.

Phototherapy with UV-A radiation and oral psoralens is another knowntreatment. UV-A irradiation occurs at intervals of two to three timesweekly and is generally maintained for months to greater than a year.Once again, the success rate is relatively low. Elliott, J., “ClinicalExperiences With Methosaxalen in the Treatment of Vitiligo”, J. InvestDermatol, 1959; 32: 311-314; Farah, F. et al, “The Treatment of Vitiligowith Psoralens and Triamcinolone By Mouth”, Br. J. Dermatol, 1969; 79:89-91; Ortonne J., “Psoralen Theraphy In Vitiligo”, Clin. Dermatol;1989; 7:120-135. Moreover, side effects of this type of PUVA includeburning, nausea, erythema, lentigenes, pruritus, and cataracts.

UVB phototherapy is much more effective at stimulating melanocytes thanPUVA. However, regular UVB light cannot penetrate the skin deeper thanthe epidermis, and hence is completely ineffective in stimulating thedeep melanocytes underneath patches of vitiligo. The present inventionovercomes this problem in the prior art through the use of an excimerlaser which emits laser light in the ultraviolet range and provideshigher energy fluences thereby decreasing the treatment time.

M. Thissen et al., Laser Treatment for Further Depigmentation inVitiligo, International Journal of Dermatology, Vol. 36 (1997) teachesthe use of a ruby laser to depigment normal skin and bleach it to awhite color. Ruby lasers, unlike excimer lasers, employ a-ruby crystalto generate laser light in the red spectrum. The laser light is used todepigment normal skin, and does not attempt to restore or treat skinareas afflicted by vitiligo. Therefore, unlike the present inventionwhich attempts to stimulate melanin production and restore pigmentation,patients subjected to the Thissen treatment end up depigmenting theirremaining normal skin. The drawbacks of this treatment are that thedepigmented skin lacks melanin and is the color white, which isgenerally less aesthetically desirable than the natural skin color ofthe patient. This depigmented skin is also more sensitive to the sunthan normally pigmented skin, and the patient with depigmented skin mustbe protected from the sun for the rest of his or her life. Finally, theThissen article acknowledges that this method is only effective invitiligo afflicted patients where the skin has become over 80%depigmented.

K. Sasaki et al., Role of Low Reactive-Level Laser Therapy (LLLT) in theTreatment of Acquired and Cicatrical Vitiligo, Laser Therapy, Vol. 1No.3 (1989) teaches use of a diode laser, either alone or in combinationwith an argon laser, to revive dormant or malfunctioning melanocytes inorder to repigment vitiligo afflicted skin areas. This technique suffersfrom the disadvantage that both the argon and diode lasers are needed inorder to treat cicatrical-type vitiligo, or vitiligo that follows afterscarring or trauma. Argon lasers also suffer from the disadvantage thatthey may cause thermal damage to the skin. In addition, argon lasers asdisclosed in Sasaki emit visible light (488 nm and 514.5 nm), whilediode lasers emit infrared light (830 nm). Unlike the present invention,these lasers do not emit UV light, and therefore do not benefit from thespecial ability UVB light has in stimulating melanocyte growth andmelanin production.

H. Yu et al, Helium-Neon Laser Treatment Induces Repigmentation inSegmental-Type Vitiligo, Journal of Investigative Dermatology, Vol.112(4) (1999) teaches use of a Helium-Neon laser that emits light in thevisible red to infrared range, as opposed to UV light. Unlike thepresent invention, Helium-Neon laser light suffers from the disadvantagethat it does not stimulate melanocytes directly, but instead inducesnerve growth. For this reason, this method of treating vitiligo isconfined to segmental-type vitiligo, which is vitiligo caused bydysfunction of nerves.

Lasers have also been used to treat vitiligo to aid in skin grafting. R.Kaufman, et al., Grafting of In Vitro Cultured Melanocytes ontoLaser-Ablated Lesions in Vitiligo, ACTA Demato-Veneriologica, Vol. 78/2(1998); J. S. Yang et al., Treatment of Vitiligo with AutologousEpidermal Grafting by Means of Pulsed Erbium: YAB Laser, Journal of theAmerican Academy of Dermatology, Vol. 38/2 (1998). Unlike the presentinvention, these techniques are invasive and require that the vitiligoaffected areas be relatively small and stable.

Narrowband UV-B phototherapy using a spectrum of 311-315 nm wavelengthwith a peak emission of 311 nm has been used to treat vitiligo.Westerhof et al. teaches the use of narrowband UV-B phototherapy atintervals of two times per week for four to twelve months. However, thismethod requires regular phototherapy sessions several times a week forup to a year to achieve a therapeutic response. UV-B phototherapy ingeneral has few side effects and is mainly limited to erythema.

What is needed is a method of treating vitiligo with UVB light thattreats only the areas of vitiligo with increased precision, at higherenergy fluences, to reduce length of treatment. What is also needed is amethod of treating vitiligo that is as effective as UVB light instimulating melanocytes, but without the disadvantage of being unable topenetrate beyond the epidermal skin layer. What is also needed is amethod of treating vitiligo that only treats the areas of the vitiligo,and not the entire body, to reduce the risk of skin cancers. Finally,what is needed is a method that restores pigmentation to skin areasafflicted with vitiligo, rather than simply covering the affected areasor bleaching normal skin white, so that the result is both morepermanent and more aesthetically pleasing.

BRIEF SUMMARY OF THE INVENTION

The present invention is a method of treating vitiligo using an excimerlaser, a laser which produces light in the UVB range. The presentinvention includes a method for treating vitiligo by incrementallyincreasing exposure of afflicted areas of skin with UVB laser light torestore the pigmentation in the areas afflicted with vitiligo. Thepresent invention overcomes the problems associated with currentvitiligo treatments through the use of an excimer laser. Laser light iscoherent and collimated whereas regular light is incoherent anddivergent, allowing laser UVB light to penetrate deeper into skin andquickly stimulate deep melanocytes underneath patches of vitiligo.Therefore unlike regular UVB light or, PUVA therapy, the presentinvention is able to better stimulate deep melanocytes, and is able todeliver higher energy fluences in less time than known treatments.Another advantage of the present invention is that laser treatment isconfined to only those areas afflicted with vitiligo, not to normalskin, and thus significantly reduces risk of skin cancers over othertypes of therapy such as PUVA treatments. Yet another advantage of thepresent invention is that the vitiligo areas are treated and madedarker, making the areas better match the natural skin color of thepatient, as opposed to simply bleaching the surrounding non-vitiligoareas to an unnatural white. Finally, the present invention changes theactual pigment of the skin, and therefore will not rub or wash-off.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 depicts vitiligo involving periocular skin in an individual withphototype V skin before treatment.

FIG. 2 depicts vitiligo involving the extensor elbow in an individualwith phototype V skin before treatment.

FIG. 3 depicts vitiligo involving the periocular skin in an individualwith phototype III skin before treatment.

FIG. 4 depicts a comparison of the number of treatments and the degreeof repigmentation in the study population.

FIG. 5 depicts complete repigmentation after 5 treatments.

FIG. 6 depicts spotty follicular repigmentation after 12 treatments.

FIG. 7 depicts focal repigmentation after 12 treatments.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a method of using UVB laser light to treatvitiligo. Laser light is different than regular light in that it iscoherent and collimated, which can be thought of as more “concentrated.”A given dose of laser light is often much more effective in producingphotochemical reactions than conventional light. Treatment of vitiligowith UVB laser light is superior because laser light 1) penetratesdeeper in the skin than conventional light, and 2) a given dose of lightis delivered much more quickly with laser light. This second effectbecomes important if stimulation of melanocytes has a time component,i.e. stimulation is more effective if done quickly.

Also claimed and disclosed is a method of using UVB laser light to treatvitiligo where the time of exposure to the vitiligo afflicted skin areasis gradually increased. A diagnosis of vitiligo is made clinically, andthe absence of melanin is confirmed by Woods light examination. A Wood'slight examination uses UV light, also known as “black light,” toaccentuate areas of white color. In the practicing invention, a patientafflicted with vitiligo is treated by exposing the afflicted area to theUVB laser beam at periodic intervals. For example, the exposure to thevitiligo afflicted skin areas can be administered between 1 to 5 timesper week. The first treatment would last for up to 5 seconds, dependingon the intensity setting of the laser beam. The greater the intensity,the shorter the exposure to the beam. The exposure time for eachtreatment would be gradually increased, to a maximum of 10 seconds.

In one embodiment of the invention, an excimer laser is used to generatethe UVB laser light. An excimer laser is a laser which uses a rare-gashalide or rare-gas metal vapor and emits laser light in the ultraviolet(126 to 558 nm) range. Currently, only excimer lasers emit laser lightin the UV range, although any future lasers that emit light in the UVBrange would also be encompassed by this invention. The laser used shouldoperate in a range between 290 and 320 nm in wavelength, the UVB rangeof light. The laser should be utilized at a setting of not more than 120mwatts.

A 308 excimer laser from the Surgilight Corporation, Winter Park Fla.,is preferred for use in practicing the present invention. This laseroperates at 308 nm via a fiber optic cable with pulse duration of 120nsec, fired at repetition rate of 20 hz. The laser spot size is 10×10mm. A photometer measures laser output, and the laser is utilized at asetting of 60 mwatts. In one preferred method of treatment, a patientwith vitiligo is exposed to the 308 nm excimer laser three times a week.The first treatment lasts 2 seconds. The patient returns, and if thereis no sunburn, the treated area is retreated again for 2 seconds. Ifthere is sunburn, treatment is withheld until the sunburn is gone. Onthe third visit, if there is no sunburn, the dose is increased to 4seconds. This is repeated the fourth visit, and then increased to 6seconds on the fifth visit. On the sixth visit, 6 seconds is givenagain. Therefore, in this preferred method, each dose is repeated once,then increased by two seconds, to a maximum of 10 seconds. Treatment iscontinued for one month, or until repigmentation occurs, which is a muchshorter time than PUVA therapy, which typically takes 6 months beforeany result is seen. Repigmentation is the appearance of brown pigment inthe treated area, and is documented by standardized photography. Inpreliminary trials, four out of five patients receiving treatment for aminimum of nine sessions showed some response. This is a significant andsubstantial improvement in success rate over PUVA, glucocortoids, or anyother current therapy for vitiligo. The repigmented skin is alsorelatively more permanent than other treatments such as sunscreens andcosmetic cover-ups, and will not rub-off.

When compared to standard phototheraphy, the 308 nm excimer laser hasthe advantage of having increased precision and the ability to deliverhigher energy fluences thereby decreasing treatment time.

EXAMPLES

The following are intended as non-limiting examples of the invention.

Six men and twelve women with multiple discreet chronic stable patchesof vitiligo enrolled in the study. Most patients had received and faileda variety of prior therapies for vitiligo (Table 1). No patient receivedany additional vitiligo therapy for at least one month prior to andduring the study.

Eighteen patients started the study with a total of twenty-nine treatedvitiligo patches. All patients had untreated vitiligo patches that wereused as controls. Test areas of vitiligo were treated using a 308-nmxenon chloride excimer laser. A 120-ns, 20-hz, pulse was used with a10-mm by 10-mm spot size and a power output of 60 mw of laser light.Lesions were treated three times a week for a maximum of 12 treatments.Exposure time was started at 2 seconds and increased by 2 seconds atevery other visit until complete repigmentation occurred or until theprotocol (12 treatments) was completed. Treatment was withheld ifsunburn was observed and held until resolution.

Treated areas were evaluated for repigmentation and erythema on separatefour point scales. Repigmentation was graded on the percentage oftreated area of repigmentation as follows: 0:0%, 1:1-25%, 2:26-75% and3:76-100%. Sunburn (erythema) was similarly graded as follows: 0-None,1-Mild, 2-Moderate, 3-Severe. Patients with no repigmentation weredefined as non-responders.

Results

Twelve patients with 23 patches completed at least six treatments. Sixpatients with 11 patches of vitiligo completed all twelve treatmentsthat required an average of four weeks to complete. Six patients droppedout of the study before completion of six treatments and resulted in oneslight repigmentation and five non-responders. Two of the non-respondersdeveloped mild erythema. Twelve patients with six or more totaltreatments of 23 vitiligo patches resulted in partial repigmentation in57% of twenty-three patches. Six patients who completed twelvetreatments of 11 vitiligo patches resulted in partial repigmentation in87% of eleven patches (FIG. 4). There were no serious adverse events.Mild sunburn with persistent erythema lasting up to three weeks wasobserved in some patients. Patients with the most repigmentation wereskin-types III-VI. Table 1 sets forth the results. TABLE 1 Demographicsand Study Results of Patients Involved In the Protocol Skin PriorTreatment Treatments % Repig- Patient Sex Phototype Treatment LocationsReceived mentation * Erythema ** 1 M V TS Periocular 5 3 0 Forearm 12 30 2 F III PUVA Periocular 12 1 0 Back 12 1 0 Hand 12 0 0 Thigh 12 1 0 3F I None L. Forearm 12 1 1 4 F III-IV None L. Preauricular 9 5 M II NoneL. Neck 3 0 1 6 F II TS. Folate L. Hand 5 1 0 7 F IV PUVA Finger 12 0 08 M II TS Abdomen 3 0 1 9 F VI TS R. Temple 2 0 0 10 F II None R. Wrist6 11 F III-IV None R. Axilla 8 1 1 Sternum 8 1 1 12 F None R. Axilla 1 00 13 M III-IV None Chin 10 0 1 L. Elbow 10 0 1 L. Arm 10 0 1 14 M IIPUVA L. periocular 10 0 1 R. Elbow 10 1 0 Chin 10 0 1 15 F II PUVA L.Shin 9 1 0 L. Elbow 9 0 1 16 F II TS Forearm 5 0 0 17 M IV PUVA Forehead12 1 0 Chin 12 1 0 18 F V None Elbow 12 2 0* Repigmentation: 0 = 0; 1 = 1-25%; 2 = 26-75%; 3 = 76-100%** Erythema: 0 = none; 1 = mild; 2 = moderate; 3 = severe

While the invention has been particularly shown and described withreference to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the spirit and scope of theinvention. All patent applications, patents, patent publications andliterature references cited in this specification are herebyincorporated by reference in their entirety.

1. A method of treating vitiligo comprising the steps of: (A)identifying an area of skin with an absence of melanin; and (B)repeatedly exposing said area of skin to laser light in the UVB range.2. The method of claim 1 wherein said laser light is generated by anexcimer laser.
 3. The method of claim 2 wherein the wavelength of saidlaser light is 308 nm, and the intensity of said laser light is 60mwatts.
 4. The method of claim 1 wherein the wavelength of said laserlight is 290 to 320 nm.
 5. The method of claim 1 wherein each exposureof said area of skin to laser light occurs for an incrementallyincreased time period.
 6. The method of claim 1 which comprisesstimulating melanin production in said area of skin with said repeatedexposures.
 7. A method of treating vitiligo comprising the steps of: (A)identifying an area of skin with an absence of melanin; (B) generatinglaser light in the UVB range using an excimer laser; and (C) repeatedlyexposing said area of skin to said excimer laser light in the UVB range.8. The method of claim 7 wherein said UVB range is between 290 and 320nm.
 9. The method of claim 7 wherein the excimer laser is a 308-nm xenonchloride excimer laser.
 10. A method of restoring pigmentation to areasof skin affected by vitiligo comprising the steps of: (A) generatinglaser light in the UVB range using an excimer laser; and (B) exposingsaid areas of skin to said laser light.
 11. A method of treatingvitiligo consisting essentially of the steps of: (A) identifying an areaof skin with an absence of melanin; and (B) repeatedly exposing saidarea of skin to laser light in the UVB range.
 12. The method of claim 1,wherein said method does not include a step of topically applying amedication to the areas of skin with an absence of melanin.
 13. Themethod of claim 12, wherein the wavelength of said light is 308 nm andthe intensity of said laser light is 60 mwatts.
 14. A method of treatingvitiligo comprising the steps of: (A) identifying an area of skin withan absence of melanin; and (B) repeatedly exposing said area of skin toUVB light, said light radiating in phase.
 15. A method of treatingvitiligo comprising the steps of: (A) identifying an area of skin withan absence of melanin; and (B) repeatedly exposing said area of skin toUVB light at a wavelength and intensity able to penetrate the epidermallayer in order to stimulate deep melanocytes underneath patches ofvitiligo.